Methods and compositions for treating infections comprising a local anesthetic

ABSTRACT

The present invention is directed to a drug depot useful for reducing, preventing or treating an infection in a patient in need of such treatment. The drug depot includes a polymer and a therapeutically effective amount of a local anesthetic or pharmaceutically acceptable salt thereof. The drug depot is administered at a site to reduce, prevent or treat an infection. The drug depot is capable of releasing (i) a bolus dose of the local anesthetic or pharmaceutically acceptable salt thereof at the site and (ii) a sustained release dose of an effective amount of the local anesthetic or pharmaceutically acceptable salt thereof over a period of at least 4 days at the site.

This application claims the benefit of the filing date of U.S.Provisional Application No. 61/140,368 filed Dec. 23, 2008 and entitled“Methods and Compositions for Treating Infections Comprising a LocalAnesthetic,” which is hereby incorporated by reference thereto.

BACKGROUND

Every year, lives are lost because of the spread of infections.Infections result from the body's inability to fight off foreignmicroorganisms or pathogens that may cause damage or disease if leftuntreated. The infecting organism or pathogen can be a bacteria, virus,fungus or some other parasite. The infecting organism or pathogen seeksto utilize the host's resources to multiply (usually at the expense ofthe host) or colonize. The infecting organism or pathogen interfereswith the normal functioning of the host and can lead to chronic wounds,gangrene, loss of an infected limb, death, etc.

There are many common infections and some very rare ones, all withvarying causes and treatments. Common bacterial infections include strepthroat, tuberculosis, urinary tract infections and microbial infectionssuch as E. coli or Staphylococcus aureus. Bacterial infections aregenerally treated with an antibiotic specifically chosen to destroy theinfectious bacteria and delivered systemically, however, antibiotics aresometimes not effective. In addition, systemically delivered antibioticsmay result in adverse side effects.

Common viral infections include a cold and influenza. Viral andbacterial infections differ in that viral infections are caused byviruses which are smaller than a bacterium or fungus. When a virusinfects healthy cells, it prevents the cells from doing their job andcauses sickness. Viruses usually infect a specific type of cell whichcauses viral infections to affect certain parts of the body. Viralinfections in some cases can be treated with antiviral drugs to stop thevirus from replication, however, antiviral drugs are not alwayseffective at preventing or stopping replication of the virus.Antibiotics are not effective against viral infections. As such, viralinfections must generally run a natural course and be fought off by thebody. However, the body sometimes has trouble fighting off the virus andthe virus could promote subsequent infection by a bacterium or fungus.

Common fungal infections include ringworm, Athlete's foot and vaginalyeast infections. Fungal infections are caused by a fungus that haseither been transmitted through contact or has grown as a result ofcertain conditions of the body. Fungal infections are treated withanti-fungal medications that may be applied as a cream or taken orally,however, these medications are also sometimes not effective and canresult in serious adverse effects.

Infections can occur in many ways including during or following surgeryand the implications can be very serious. Antibiotics have been usedprior to and after surgery to treat infections, however, as statedabove, antibiotics are not always effective and if the pathogen is notbacterial, the antibiotic will not be effective. In addition, if aninfection occurs during surgery, a systemically administered antibioticmay not be effective quickly enough and a physician may need to accessthe site of infection to try to treat the infection.

Anesthetics are generally a class of drugs or agents that produce alocal or general loss of sensation, including pain, and therefore areuseful in surgery and dentistry. Local anesthetics are drugs or agentsthat cause reversible local anesthesia and a loss of nociception. Localanesthetics act mainly by reversibly binding to and inactivating sodiumchannels thereby inhibiting sodium influx through sodium-specific ionchannels in the neuronal cell membrane. Sodium influx through thesechannels is necessary for the depolarization of nerve cell membranes andsubsequent propagation of impulses along the course of the nerve. When anerve loses depolarization and capacity to propagate an impulse, theindividual loses sensation in the area supplied by the nerve. Localanesthetics are typically known for infiltration, epidural block andspinal anesthesia. Local anesthetics are not known for treating orpreventing infections.

One local anesthetic that is known to the medical profession isbupivacaine, which is widely recognized as a local anesthetic forinfiltration, nerve block, epidural and intrathecal administration. Ingeneral, bupivacaine, also referred to as1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (C₁₈H₂₈N₂O) maybe represented by the following structure:

Bupivacaine has not been used nor known for treating or preventinginfections. Rather, bupivacaine is often administered by epiduralinjection before total hip arthroplasty or injected to surgical woundsites to reduce pain after a surgery.

As the presently available treatments for several types of infectionsare sometimes not effective and cause undesirable side effects, thereexists a need to prevent, treat or reduce infections using a medicationthat causes minimum or no side effects. New compositions comprising alocal anesthetic are provided that effectively prevent, treat or reduceinfections while causing minimum or no side effects.

SUMMARY

New compositions and methods are provided that effectively prevent,treat or reduce infections. The compositions and methods prevent, treator reduce infections via a single drug depot or multiple drug depots.The compositions and methods allow accurate and precise administrationof the drug depot(s) including an analgesic with minimal physical andpsychological trauma to a patient. The drug depot(s) can be easilydelivered to the target site (e.g., wound site, abdomen, synovial joint,at or near the spinal column, etc.) and treat infections for at least 4to 10 days. In this way, accurate and precise administration of the drugdepot(s) in a minimally invasive procedure can be accomplished.

In one embodiment, a drug depot useful for reducing, preventing ortreating an infection in a patient in need of such treatment isprovided. The drug depot comprises a therapeutically effective amount ofan analgesic, local anesthetic or pharmaceutically acceptable saltthereof and the depot is administered at a site to reduce, prevent ortreat an infection. The drug depot is capable of releasing an effectiveamount of the analgesic, local anesthetic or pharmaceutically acceptablesalt thereof over a period of at least 4 days. The drug depot in thisembodiment may be capable of releasing (i) a bolus dose of theanalgesic, local anesthetic or pharmaceutically acceptable salt thereofat the site to reduce, prevent or treat an infection and (ii) asustained release dose of an effective amount of the analgesic, localanesthetic or pharmaceutically acceptable salt thereof over a period ofat least 4 days at the site to treat, reduce or prevent the infection.The bolus dose provides immediate relief to an existing infectionfollowed by continuous treatment during at least 4 days. The drug depotmay comprise a polymer. The drug depot can be a ribbon-like strip orfiber that releases the analgesic or local anesthetic over the period ofat least 4 days. The drug depot can also be a gel formulation thatreleases the analgesic or local anesthetic over the period of at least 4days.

In another embodiment, a method of making a drug depot is provided. Themethod comprises combining a biocompatible polymer and a therapeuticallyeffective amount of local anesthetic or pharmaceutically acceptable saltthereof and forming the drug depot from the combination.

In yet another embodiment, a method of treating or preventing infectionsin a patient in need of such treatment is provided. The method comprisesadministering one or more biodegradable drug depots comprising atherapeutically effective amount of an analgesic, local anesthetic orpharmaceutically acceptable salt thereof to a target site, wherein thedrug depot releases an effective amount of the analgesic, localanesthetic or pharmaceutically acceptable salt thereof over a period ofat least 4 days. The drug depot may be capable of releasing (i) a bolusdose of the analgesic, local anesthetic or pharmaceutically acceptablesalt thereof at a site and (ii) a sustained release dose of an effectiveamount of the analgesic, local anesthetic or pharmaceutically acceptablesalt thereof over a period of at least 4 days at the site. The bolusdose provides immediate relief to an existing infection followed bycontinuous treatment during at least 4 days. The drug depot may comprisea polymer. The drug depot can be a ribbon-like strip that releases theanalgesic or local anesthetic over the period of at least 4 days. Thedrug depot can also be a gel formulation that releases the analgesic orlocal anesthetic over the period of at least 4 days.

In still yet another embodiment, a drug depot useful for reducing,preventing or treating an infection in a patient in need of suchtreatment is provided. The drug depot comprises a therapeuticallyeffective amount of bupivacaine or pharmaceutically acceptable saltthereof and a polymer. The depot is administered at a target site toreduce, prevent or treat an infection. The depot is capable of releasing(i) about 2% to about 50% of the bupivacaine or pharmaceuticallyacceptable salt thereof relative to a total amount of the bupivacaine orpharmaceutically acceptable salt thereof loaded in the drug depot over afirst period of up to 48 hours, a first period of up to 24 hours, or afirst period of about 24 to 48 hours and (ii) about 50% to about 98% ofthe bupivacaine or pharmaceutically acceptable salt thereof relative toa total amount of the bupivacaine or pharmaceutically acceptable saltthereof loaded in the drug depot over a subsequent period of up to 3 to30 days, 2 to 10 days or 3 to 10 days. In various embodiments, when thefirst period is up to 24 hours or about 24 to 48 hours, the depot iscapable of releasing about 2% to about 40% of the bupivacaine orpharmaceutically acceptable salt thereof.

In another embodiment, a drug depot for reducing, preventing or treatingan infection in a patient in need of such treatment is provided. Thedrug depot comprises: (i) bupivacaine or pharmaceutically acceptablesalt thereof at an amount of about 30 wt. % to about 90 wt. % of thedrug depot; and (ii) at least one biodegradable material. The depot iscapable of releasing an initial bolus dose of bupivacaine orpharmaceutically acceptable salt thereof at a site, and the depot iscapable of releasing a sustained release dose of an effective amount ofbupivacaine or pharmaceutically acceptable salt thereof over asubsequent period of at least 4 days, 4 to 30 days or 4 to 10 days. Thebolus dose provides immediate relief to an existing infection followedby continuous treatment during the subsequent period. The drug depot iscapable of releasing about 40% to about 70% of the bupivacaine orpharmaceutically acceptable salt thereof relative to a total amount ofbupivacaine loaded in the drug depot over the sustained release periodof at least 4 days, 4 to 30 days or 4 to 10 days after the drug depot isadministered. The biodegradable material comprises one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. In various embodiments, the biodegradable materialcomprises a polymer comprising poly(lactic-co-glycolic acid) orpoly(orthoester) or both. In some embodiments, the biodegradablematerial comprises a polymer comprising poly(lactic-co-glycolic acid)wherein the poly(lactic-co-glycolic acid) comprises a mixture ofpolyglycolide and polylactide. The polymer can comprise more polylactidethan polyglycolide.

In still another embodiment, the drug depot comprises an analgesic, apolymer and further an excipient. The drug depot may comprise ananalgesic in an amount of about 30 to about 90 weight percent (wt. %),about 10 to about 80 wt. % of a polymer and about 0.5 to about 20 wt. %of an excipient. For example, the drug depot can include a localanesthetic at an amount of about 30 to about 90 wt. % of the drug depot,about 10 to about 80 wt. % PLGA and about 0.5 to about 20 wt. % mPEG.

In various embodiments, the analgesic may be a local anesthetic or apharmaceutically acceptable salt thereof and the local anesthetic may beat least one of bupivacaine, ropivacaine, mepivacaine, etidocaine,levobupivacaine, trimecaine, carticaine or articaine. Bupivacaine may bein the form of a salt and/or in the form of a base. The local anestheticor pharmaceutically acceptable salt thereof may be encapsulated in aplurality of depots comprising microparticles, microspheres,microcapsules, and/or microfibers suspended in a gel.

The drug depot in various embodiments is capable of releasing aneffective amount of the analgesic, local anesthetic or pharmaceuticallyacceptable salt thereof over a period of at least 4 days. For example,the drug depot may release about 40% to about 70% of the analgesic,local anesthetic or pharmaceutically acceptable salt thereof relative toa total amount of the analgesic or local anesthetic loaded in the drugdepot over a period of 4 to 10 days after the drug depot is administeredto a target site. The analgesic or local anesthetic is released in anamount between 50 and 800 mg per day during this period of 4 to 10 days.The drug depot, though, is capable of releasing an effective amount ofthe analgesic, local anesthetic or pharmaceutically acceptable saltthereof over a much greater period, e.g., at least 7 days and in therange of 7 to 30 days, after the drug depot is administered to the site.

The polymer in various embodiments comprises one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. The polymer(s) may be biodegradable. Further, ifthe polymer(s) are biodegradable, the polymer(s) may be capable ofdegrading or degrade in 30 days or less after the drug depot isadministered at a site.

The target site can be a wound site, a muscle, a ligament, a tendon,cartilage, a spinal disc, the spinal foraminal space near the spinalnerve root, a facet or synovial joint, or the spinal canal.

The infection may result or be associated with hernia repair, orthopedicor spine surgery or a combination thereof. The surgery may bearthroscopic surgery, an excision of a mass, hernia repair, spinalfusion, thoracic, cervical, or lumbar surgery, pelvic surgery or acombination thereof.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a number of common locations within a patient thatmay be sites where surgery is conducted and locations where the drugdepot containing an analgesic or local anesthetic can be administeredthereto.

FIG. 2 illustrates a schematic dorsal view of the spine and sites wherea drug depot containing an analgesic or local anesthetic can beadministered thereto.

FIG. 3 is a graphic representation of a study of the cumulative releasein ug of bupivacaine sterilized formulations.

FIG. 4 is a graphic representation of a study of the percentagecumulative release of sterilized bupivacaine formulations.

FIG. 5 is a graphic representation of the cumulative in vitro releaseprofile for certain bupivacaine formulations.

FIG. 6 is a graphic representation of the cumulative daily releaseprofiles for the certain bupivacaine formulations illustrated in FIG. 5.

FIG. 7 is a graphic representation of the cumulative in vitro releaseprofile for bupivacaine formulations from a study described in Example4.

FIG. 8 is a graphic representation of the cumulative in vitro releaseprofile for bupivacaine formulations from a study described in Example4.

FIG. 9 is a graphic representation of the cumulative in vitro releaseprofile for another bupivacaine formulation from a study described inExample 4.

FIG. 10 is a graphic representation of the cumulative in vitro releaseprofile for bupivacaine formulations from a study described in Example5.

FIG. 11 is a graphic representation of the cumulative in vitro releaseprofile for bupivacaine formulations from a study described in Example5.

FIG. 12A is a graphic representation of the percentage cumulativerelease for three bupivacaine strips from a study described in Example6.

FIG. 12B is a graphic representation of the average percentagecumulative release for the bupivacaine strips shown in FIG. 12A.

FIG. 13A is a graphic representation of the cumulative in vitro releasein ug for the three bupivacaine strips described in Example 6.

FIG. 13B is a graphic representation of the average cumulative in vitrorelease in ug for the bupivacaine strips shown in FIG. 13A.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents, which may be included within the invention as defined bythe appended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

New compositions and methods are provided that effectively prevent,treat or reduce an infection. The compositions and methods prevent,treat or reduce infections by administration of a single drug depot ormultiple drug depots. The compositions and methods allow accurate andprecise administration of the drug depot(s) including an analgesic suchas bupivacaine with minimal physical and psychological trauma to apatient. The drug depot(s) can be easily delivered to the target site(e.g., wound site, abdomen, synovial joint, at or near the spinalcolumn, etc.) and alleviate and/or treat an infection for at least 4 to10 days. In this way, accurate and precise administration of the drugdepot(s) in a minimally invasive procedure can be accomplished.

Bupivacaine

Bupivacaine or another local anesthetic may be contained in a drugdepot. A drug depot comprises a physical structure to facilitateadministration and retention in a desired site (e.g., a wound site, asynovial joint, a disc space, a spinal canal, abdominal area, a tissueof the patient, etc.). The drug depot also comprises the drug. The term“drug” as used herein is generally meant to refer to any substance thatalters the physiology of a patient. The term “drug” may be usedinterchangeably herein with the terms “therapeutic agent”,“therapeutically effective amount”, and “active pharmaceuticalingredient” or “API”. It will be understood that a “drug” formulationmay include more than one therapeutic agent, wherein exemplarycombinations of therapeutic agents include a combination of two or moredrugs. The drug depot provides a concentration gradient of thetherapeutic agent for delivery to the site. In various embodiments, thedrug depot provides an optimal drug concentration gradient of thetherapeutic agent at a distance of up to about 1 cm to about 10 cm fromthe implant site.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of an infection, reduction oralleviation of an infection, improvement in the condition, etc. Invarious embodiments, the therapeutically effective amount of bupivacainecomprises from about 0.5 mg to 1,000 mg/day. In some embodiments, thetherapeutically effective amount of bupivacaine comprises from about 0.1mg to 800 mg of bupivacaine per day. In some embodiments, thetherapeutically effective amount of bupivacaine comprises from about 50mg to 800 mg of bupivacaine per day or from about 200 mg to 800 mg ofbupivacaine per day. In some embodiments, the therapeutically effectiveamount of bupivacaine comprises about 0.5 mg, 100 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1,000 mg ofbupivacaine per day and all subranges therebetween. In some embodiments,the therapeutically effective amount of bupivacaine comprises 0.5 mg,0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg,18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, or40 mg of bupivacaine per day. In one embodiment, the dosage to a humanis between 400 mg and 600 mg of bupivacaine per day. It will beunderstood that the dosage administered to a patient can be as a singledepot or multiple depots depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired. For example, lower dailydoses of bupivacaine may be needed when there is concurrent treatment.

In various embodiments, a therapeutically effective amount ofbupivacaine is provided to inhibit, treat and/or prevent an infection.In general, the chemical name of bupivacaine is1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide. Bupivacaine hasa molecular weight of 288.43 and exhibits the following generalstructure:

Bupivacaine includes, but is not limited to,(+/−)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide orpharmaceutically acceptable non-toxic esters or salts thereof.Bupivacaine includes the racemic mixtures ((+)-R and (−)-S enantiomers)or each of the dextro and levo isomers of bupivacaine individually.Bupivacaine includes the free acid as well as any other pharmaceuticallyacceptable salt of any one of the foregoing. Bupivacaine may also bepegylated for long acting activity.

Pharmaceutically acceptable esters of bupivacaine include but are notlimited to, alkyl esters derived from hydrocarbons of branched orstraight chain having one to about 12 carbon atoms. Examples of suchesters are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isoamyl,pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl ordodecyl esters.

Pharmaceutically acceptable salts of bupivacaine include salts derivedfrom either inorganic or organic bases. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, ferrous, zinc, copper, manganese,aluminum, ferric, manganic salts or the like. Salts derived frompharmaceutically acceptable organic non-toxic bases include, but are notlimited to, salts of primary, secondary, or tertiary amines, substitutedamines including naturally occurring substituted amines or cyclic aminesor basic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins or the like.

In addition to bupivacaine, the drug depot may comprise one or moreadditional therapeutic agents. Examples of therapeutic agents include,those that are direct- and local-acting modulators of pro-inflammatorycytokines such as TNF-α and IL-1 including, but not limited to, solubletumor necrosis factor α receptors, any pegylated soluble tumor necrosisfactor α receptor, monoclonal or polyclonal antibodies or antibodyfragments or combinations thereof. Examples of suitable therapeuticagents include receptor antagonists, molecules that compete with thereceptor for binding to the target molecule, antisense polynucleotides,and inhibitors of transcription of the DNA encoding the target protein.Suitable examples include but are not limited to Adalimumab, Infliximab,Etanercept, Pegsunercept (PEG sTNF-R1), sTNF-R1, CDP-870, CDP-571,CNI-1493, RDP58, ISIS 104838, 1→3-β-D-glucans, Lenercept, PEG-sTNFRII FcMutein, D2E7, Afelimomab, and combinations thereof. In otherembodiments, a therapeutic agent includes metalloprotease inhibitors,glutamate antagonists, glial cell-derived neurotropic factors (GDNF), B2receptor antagonists, Substance P receptor (NK1) antagonists such ascapsaicin and civamide, downstream regulatory element antagonisticmodulator (DREAM), iNOS, inhibitors of tetrodotoxin (TTX)-resistantNa+-channel receptor subtypes PN3 and SNS2, inhibitors of interleukinssuch as IL-1, IL-6 and IL-8, and anti-inflammatory cytokines, TNFbinding protein, onercept (r-hTBP-1), recombinant adeno-associated viral(rAAV) vectors encoding inhibitors, enhancers, potentiators, orneutralizers, antibodies, including but not limited to naturallyoccurring or synthetic, double-chain, single-chain, or fragmentsthereof. For example, suitable therapeutic agents include molecules thatare based on single chain antibodies called Nanobodies™ (Ablynx, GhentBelgium), which are defined as the smallest functional fragment of anaturally occurring, single-domain antibody. Alternatively, therapeuticagents include, agents that effect kinases and/or inhibit cell signalingmitogen-activated protein kinases (MAPK), p38 MAPK, Src or proteintyrosine kinase (PTK). Therapeutic agents include, kinase inhibitorssuch as, for example, Gleevec, Herceptin, Iressa, imatinib (STI571),herbimycin A, tyrphostin 47, erbstatin, genistein, staurosporine,PD98059, SB203580, CNI-1493, VX-50/702 (Vertex/Kissei), SB203580, BIRB796 (Boehringer Ingelheim), Glaxo P38 MAP Kinase inhibitor, RWJ67657(J&J), UO126, Gd, SCIO-469 (Scios), RO3201195 (Roche), Semipimod(Cytokine PharmaSciences), or derivatives thereof.

Therapeutic agents, in various embodiments, block the transcription ortranslation of TNF-α or other proteins in the inflammation cascade.Suitable therapeutic agents include, but are not limited to, integrinantagonists, alpha-4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, CTLA4-Ig agonists/antagonists(BMS-188667), CD40 ligand antagonists, Humanized anti-IL-6 mAb (MRA,Tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics Inc.), anti-IL2Rantibodies (daclizumab, basilicimab), ABX (anti IL-8 antibodies),recombinant human IL-10, or HuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such asKineret® (anakinra) which is a recombinant, non-glycosylated form of thehuman interleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogues (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression),and aurin-tricarboxylic acid (which inhibits TNF-α), for example, mayalso be useful as therapeutic agents for reducing inflammation. It iscontemplated that where desirable a pegylated form of the above may beused. Examples of other therapeutic agents include NF kappa B inhibitorssuch as glucocorticoids, clonidine; antioxidants, such asdithiocarbamate, and other compounds, such as, for example,sulfasalazine.

Specific examples of therapeutic agents suitable for use include, butare not limited to, an anti-inflammatory agent, analgesic agent, orosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, salicylates, diflunisal,sulfasalazine, indomethacin, ibuprofen, naproxen, tolmetin, diclofenac,ketoprofen, fenamates (mefenamic acid, meclofenamic acid), enolic acids(piroxicam, meloxicam), nabumetone, celecoxib, etodolac, nimesulide,apazone, gold, sulindac or tepoxalin; antioxidants, such asdithiocarbamate, and other compounds such assulfasalazine[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid], steroids, such as fluocinolone, cortisol, cortisone,hydrocortisone, fludrocortisone, prednisone, prednisolone,methylprednisolone, triamcinolone, betamethasone, dexamethasone,beclomethasone, fluticasone or a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Additional analgesic agents may also be included in the depot. Suitableanalgesic agents include, but are not limited to, acetaminophen,lidocaine, opioid analgesics such as buprenorphine, butorphanol,dextromoramide, dezocine, dextropropoxyphene, diamorphine, fentanyl,alfentanil, sufentanil, hydrocodone, hydromorphone, ketobemidone,levomethadyl, mepiridine, methadone, morphine, nalbuphine, opium,oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol,codeine, dihydrocodeine, meptazinol, dezocine, eptazocine, flupirtine ora combination thereof.

Suitable analgesics also include agents with analgesic properties, suchas for example, amitriptyline, carbamazepine, gabapentin, pregabalin,clonidine, or a combination thereof.

The depot may contain a muscle relaxant. Exemplary muscle relaxantsinclude by way of example and not limitation, alcuronium chloride,atracurium bescylate, baclofen, carbolonium, carisoprodol, chlorphenesincarbamate, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium, orcombinations thereof.

The depot comprises the therapeutic agent or agents and may also containother non-active ingredients. These non-active ingredients may have amulti-functional purpose including the carrying, stabilizing andcontrolling of the release of the therapeutic agent(s). The sustainedrelease process, for example, may be by a solution-diffusion mechanismor it may be governed by an erosion-controlled process. Typically, thedepot will be a solid or semi-solid formulation comprised of abiocompatible material, which can be biodegradable. The term “solid” isintended to mean a non-gel like material, while, “semi-solid” isintended to mean a gel like material that has some degree offlowability, thereby allowing the depot to bend and conform to thesurrounding tissue requirements. The term “gel” is intended to mean amaterial that is soft and deformable at any point in its application tothe surgical site.

In various embodiments, the depot material will be durable on or withinthe target site for a period of time similar to (for biodegradablecomponents) or greater than (for non-biodegradable components) theplanned period of drug delivery. For example, the depot material mayhave a melting point or glass transition temperature close to or higherthan body temperature, but lower then the decomposition or degradationtemperature of the therapeutic agent. However, the pre-determinederosion of the depot material can also be used to provide for slowrelease of the loaded therapeutic agent(s).

In various embodiments, the drug depot may be designed to release thelocal anesthetic such as bupivacaine when certain trigger points arereached (e.g., temperature, pH, etc.) when implanted in vivo. Forexample, the drug depot may comprise polymers that will release moredrug as the body temperature reaches greater than, for example, 102° F.,particularly if the drug possesses antipyretic properties. In variousembodiments, depending on the site of administration, the drug depot mayrelease more or less drug as a certain pH is reached. For example, thedrug depot may be designed to release the drug as the bodily fluidhaving a certain pH contact the drug depot (e.g., CSF having a pH ofabout 7.35 to about 7.70, synovial fluid having a pH of about 7.29 toabout 7.45; urine having a pH of about 4.6 to about 8.0, pleural fluidshaving a pH of about 7.2 to about 7.4, blood having a pH of about 7.35to about 7.45, etc.).

In various embodiments, the depot may have a high drug loading, suchthat the local anesthetic such as bupivacaine and/or other therapeuticagent comprises about 5-99 wt. % of the depot, or 30-95 wt. % of thedepot, 30-90 wt. % of the depot, or 50-75 wt. % of the depot, or 55-65wt. % of the depot. In various embodiments, the amount of bupivacaineand/or other therapeutic agent are present in the depot in a range fromabout 40% to about 80% by weight of the depot (including 40%, 41%, 42%,43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, and any ranges betweenany two of these points, for instance, 40.1-50%, 50-60% and 60-70%,etc.).

In various embodiments, the drug depot may release 0.1 mg, 0.2 mg, 0.3mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 3 mg,4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg,15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25mg, 30 mg, 35 mg, or 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg,120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg,165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg, 700 mg 800 mg, 900 mg, or 1,000 mg ofbupivacaine per day and all subranges therebetween for a total of atleast 4 days, at least 7 days, at least 8 days, 4 to 30 days, 4 to 10days, 4 to 8 days, 5 to 7 days, or 7 to 10 days. In various embodiments,the drug depot may release 0.5 mg to 20 mg of bupivacaine per hour for atotal of at least 4 days, 4 to 10 days, 5 to 7 days or 7 to 10 days toreduce, treat or prevent an infection. In various embodiments, the drugdepot releases 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of the bupivacaineover a period of 3 to 10 days, 4 to 10 days, or 5 to 7 days after thedrug depot is administered to the target site. The drug depot may have a“release rate profile” that refers to the percentage of activeingredient that is released over fixed units of time, e.g., mg/hr,mg/day, 10% per day for ten days, etc. As persons of ordinary skillknow, a release rate profile may be but need not be linear. By way of anon-limiting example, the drug depot may be a strip or a ribbon-likestrip or fiber that releases the bupivacaine over a period of time.

In various embodiments, the drug depot comprises from about 40% to 80%by weight bupivacaine, 15% to 55% by weight of a polymer and 5% to 15%by weight of an excipient. mPEG may be used as an excipient orplasticizer for a polymer as it imparts malleability to the resultingformulation. PEG 300 may also be used as an excipient. In addition, acombination of PEG 300 and NMP may be used as the excipient.

Exemplary excipients that may be formulated with bupivacaine in additionto the biodegradable polymer include but are not limited to MgO (e.g., 1wt. %), 5050 DLG 6E, 5050 DLG 1A, mPEG, TBO-Ac, mPEG, Span-65, Span-85,pluronic F127, TBO-Ac, sorbital, cyclodextrin, maltodextrin andcombinations thereof. In some embodiments, the excipient or excipientsmay comprise from about 0.001 wt. % to about 50 wt. % of theformulation. In some embodiments, the excipient(s) comprise from about0.001 wt. % to about 40 wt. % of the formulation. In some embodiments,the excipient(s) comprise from about 0.001 wt. % to about 30 wt. % ofthe formulation. In some embodiments, the excipient(s) comprise fromabout 0.001 wt. % to about 20 wt. % of the formulation. In someembodiments, the excipient(s) comprise from about 0.5 wt. % to about 20wt. % of the formulation. In some embodiments, the excipient(s) comprisefrom about 0.001 wt. % to about 10 wt. % of the formulation. In someembodiments, the excipient(s) comprise from about 0.001 wt. % to about 2wt. % of the formulation.

In some embodiments, the drug depot may not be biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics or combinations thereof. Typically, these types of drug depotsmay need to be removed after a certain amount of time afteradministration.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the drug depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at a targetsite. As a function of the chemistry of the biodegradable material, themechanism of the degradation process can be hydrolytical or enzymaticalin nature, or both. In various embodiments, the degradation can occureither at the surface (heterogeneous or surface erosion) or uniformlythroughout the drug delivery system depot (homogeneous or bulk erosion).

The drug depot may comprise a polymeric or non-polymeric material aswell as a synthetic or naturally occurring material, or a combinationthereof. Non-polymeric materials include, for example, cholesterol,stigmasterol, glycerol, estradiol, sucrose, distearate, sorbitan,sorbitan monooleate, sorbitan monopalmitate, sorbitan tristearate, orthe like.

In various embodiments, the drug depot comprises a polymer and thepolymer can degrade in vivo over a period of less than a year, with atleast 50% of the polymer degrading within six months or less. In someembodiments, the polymer is capable of or will degrade in two months,one month or less. In some embodiments, the polymer will degradesignificantly within a month, with at least 50% of the polymer degradinginto non-toxic residues which are removed by the body, and 100% of thedrug being released within a two week period. Polymers should alsodegrade by hydrolysis by surface erosion, rather than by bulk erosion,so that release is not only sustained but also linear. Polymers whichmeet this criteria include some of the polyanhydrides, co-polymers oflactic acid and glycolic acid wherein the weight ratio of lactic acid toglycolic acid is no more than 4:1 (i.e., 80% or less lactic acid to 20%or more glycolic acid by weight), and polyorthoesters containing acatalyst or degradation enhancing compound, for example, containing atleast 1% by weight anhydride catalyst such as maleic anhydride. Otherpolymers include protein polymers such as gelatin and fibrin andpolysaccharides such as hyaluronic acid.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers, particles, nanospheres,nanoparticles, coatings, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, sheets, strips, ribbon-like strips or fibers, mesh,a paste, a slab, pellets, gels, or other pharmaceutical deliverycompositions. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, gel, etc.) can break down or degrade on orwithin the body to non-toxic components after or while a therapeuticagent has been or is being released. By “bioerodible,” it is meant thatthe depot and/or gel will erode or degrade over time due, at least inpart, to contact with substances found in the surrounding tissue, fluidsor by cellular action. By “bioabsorbable,” it is meant that the depotwill be broken down and absorbed on or within the human body, forexample, by a cell or tissue. “Biocompatible” means that the depot willnot cause substantial tissue irritation or necrosis at the target site.

In various embodiments, the depot may comprise a bioabsorbable, abioerodible, and/or a biodegradable biopolymer that may provideimmediate release, sustained release or controlled release of the drug.Examples of suitable sustained release biopolymers include but are notlimited to poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGAor DLG) (which includes poly(lactide-co-glycolide),poly(D-lactide-co-glycolide), poly(L-lactide-co-glycolide) andpoly(D,L-lactide-co-glycolide), polylactide (PLA), polyglycolide (PG),polyorthoester(s) (POE), polyethylene glycol (PEG), PEG 200, PEG 300,PEG 400, PEG 500, PEG 550, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000,PEG 1450, PEG 3350, PEG 4500, PEG 8000, conjugates of poly(alpha-hydroxyacids), polyaspirins, polyphosphagenes, collagen, starch,pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates,albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate,d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide,D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone(DL-G-CL), dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA),PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates,poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate)hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or salts thereof, Carbopol,poly(hydroxyethylmethacrylate), poly(methoxyethylmethacrylate),poly(methoxyethoxy-ethylmethacrylate), polymethylmethacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,or combinations thereof.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

In some embodiments, the polymer comprises PLGA or POE or a combinationthereof. The PLGA may comprise a mixture of polyglycolide andpolylactide and in some embodiments, in the mixture, there is morepolylactide than polyglycolide. In various embodiments, there is 100%polylactide and 0% polyglycolide; 95% polylactide and 5% polyglycolide;90% polylactide and 10% polyglycolide; 85% polylactide and 15%polyglycolide; 80% polylactide and 20% polyglycolide; 75% polylactideand 25% polyglycolide; 70% polylactide and 30% polyglycolide; 65%polylactide and 35% polyglycolide; 60% polylactide and 40%polyglycolide; 55% polylactide and 45% polyglycolide; 50% polylactideand 50% polyglycolide; 45% polylactide and 55% polyglycolide; 40%polylactide and 60% polyglycolide; 35% polylactide and 65%polyglycolide; 30% polylactide and 70% polyglycolide; 25% polylactideand 75% polyglycolide; 20% polylactide and 80% polyglycolide; 15%polylactide and 85% polyglycolide; 10% polylactide and 90%polyglycolide; 5% polylactide and 95% polyglycolide; and 0% polylactideand 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, when the drug depot comprises a polymer, it isemployed at about 10 wt. % to about 90 wt. %, about 10 wt. % to about 80wt. %, about 10 wt. % to about 70 wt. %, about 15 wt. % to about 55 wt.%, about 10 wt. % to about 50 wt. %, about 25 wt. % to about 45 wt. %,about 30 wt. % to about 35 wt. % or about 20 wt. % to about 40 wt. %based on the weight of the drug depot.

In some embodiments, at least 75% of the particles have a size fromabout 1 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 1 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 1 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 1 micrometer toabout 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometers to about 100 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 100 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometers to about 100micrometers. In some embodiments, all of the particles have a size fromabout 20 micrometers to about 100 micrometers.

In some embodiments, the polymer comprises DL-CL or a combinationthereof. The DL-CL may comprise a mixture of lactide and caprolactone.The molar ratio of lactide to caprolactone can be 10:90 to 90:10 and allsubranges therebetween (e.g., 20:80, 30:70, 45:55, 65:35, 67:33, 89:11,etc.).

In some embodiments, the polymer comprises DL-G-CL or a combinationthereof. The DL-G-CL may comprise a mixture of lactide, glycolide andcaprolactone. In some embodiments, the molar ratio of lactide toglycolide to caprolactone may be 30:20:50. In some embodiments, themixture may comprise 5-50% lactide, 5-50% glycolide, and 20-80%caprolactone.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfite,sodium bisulfate, sodium thiosulfate, thimerosal, methyl and otherparaben, polyvinyl alcohol and phenylethyl alcohol; solubility adjustingagents; stabilizers; and/or cohesion modifiers. Typically, any suchinactive materials will be present within the range of 0-75 wt. %, andmore typically within the range of 0-30 wt. %. If the depot is to beplaced in the spinal area or joint area, in various embodiments, thedepot may comprise sterile preservative free material.

The depot can be of different sizes, shapes and configurations. Thereare several factors that can be taken into consideration in determiningthe size, shape and configuration of the drug depot. For example, boththe size and shape may allow for ease in positioning the drug depot atthe target site that is selected as the administration, implantation orinjection site. In addition, the shape and size of the system should beselected so as to minimize or prevent the drug depot from moving afteradministration, implantation or injection. In various embodiments, thedrug depot can be shaped like a sphere, a cylinder such as a rod orfiber, a flat surface such as a disc, film, ribbon, strip or sheet, apaste, a slab, microparticles, nanoparticles, pellets, mesh or the like.Flexibility may be a consideration so as to facilitate placement of thedrug depot. In various embodiments, the drug depot can be differentsizes, for example, the drug depot may be a length of from about 0.5 mmto 100 mm and have a diameter or thickness of from about 0.01 to about 5mm. In various embodiments, the drug depot may have a layer thickness offrom about 0.005 to 5.0 mm, such as, for example, from 0.05 to 2.0 mm.In some embodiments, the shape may be a strip or a ribbon-like strip andthe strip or ribbon-like strip has a ratio of width to thickness in therange of 2 to 20 or greater.

Radiographic markers can be included on or in the drug depot to permitthe user to accurately position the depot into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium, and/or metal beads or particles. Where present, theradiographic marker is typically present in an amount of from about 10%to about 40% (including 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,33%, 34%, 35%, 36%, 37%, 38%, 39% and 40%, as well as ranges between anytwo of these values, e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-35%,35-40%, and so forth, with 15-30% being more typical, even moretypically 20-25%). In various embodiments, the radiographic marker couldbe a spherical shape or a ring around the depot.

In some embodiments, the drug depot has pores that allow release of thedrug from the depot. The drug depot will allow fluid in the depot todisplace the drug. However, cell infiltration into the depot will beprevented by the size of the pores of the depot. In this way, in someembodiments, the depot will not function as a tissue scaffold and willnot allow tissue growth. Rather, the drug depot will be utilized fordrug delivery. Thus, the drug depot will have pore sizes less than 250microns or 500 microns so as to prevent influx of cells so that the drugdepot does not function as a tissue scaffold. In other embodiments, thedepot has no pores and degrades based on the action of enzymes, byhydrolytic action and/or by other similar mechanisms in the human body.In other embodiments, the drug depot may have pore sizes above 500microns to allow influx of cells and drug release and the drug depot mayfunction, in this embodiment, as a tissue scaffold.

In one embodiment, a drug depot for delivering a therapeutic agent to atarget tissue site beneath the skin of a patient is provided, the drugdepot comprising an effective amount of bupivacaine, wherein the targettissue site comprises at least one muscle, ligament, tendon, cartilage,spinal disc, spinal foraminal space near the spinal nerve root, facet orsynovial joint, or spinal canal. The target tissue site may comprise aninfection or the depot may be implanted at the site to prevent aninfection.

In various embodiments, the drug depot comprises a gel, which includes asubstance having gelatinous, jelly-like, or colloidal properties at roomtemperature. The gel, in various embodiments, may have the bupivacaineand optionally one or more additional therapeutic agents dispersedthroughout it or suspended within the gel. The dispersal of thetherapeutic agent may be even throughout the gel. Alternatively, theconcentration of the therapeutic agent may vary throughout it. As thebiodegradable material of the gel or drug depot degrades at the site,the therapeutic agent is released.

When the drug depot is a gel, in contrast to a sprayable gel thattypically employs a low viscosity polymer, a gel with a higher viscositymay be desirable for other applications, for example, a gel having aputty-like consistency may be more preferable for bone regenerationapplications. In various embodiments, when a polymer is employed in thegel, the polymeric composition includes about 10 wt. % to about 50 wt. %or about 15 wt. % to about 30 wt. % of the polymer.

In another embodiment, the gel is in viscous form and is loaded with oneor more drug depots (e.g., microspheres loaded with a therapeuticagent), wherein the viscous gel is positioned into an infected site suchas a wound site, synovial joint, disc space, a spinal canal, or a softtissue surrounding the spinal canal of a subject. The gel can also beused, in various embodiments, to seal or repair tissue. In yet anotherembodiment, the gel is injectable, and/or an adherent gel thatsolidifies upon contact with tissue. For example, the gel may beadministered as a liquid that gels in situ at the target tissue site. Invarious embodiments, the gel can comprise a two part system where aliquid is administered and a gelling agent is added subsequently tocause the liquid to gel or harden.

In various embodiments, the gel is a hardening gel, where after the gelis applied to the target site, it hardens and the drug can be releasedas the bodily fluid contacts the gel.

In various embodiments, the drug depot is loaded with bupivacaine andoptionally one or more additional therapeutic agents, and delivered to adesired target tissue site (e.g., infected surgical wound site, infectedtissue site, etc.) and, in various embodiments, the drug depot may beheld in place by a suture, barb, staple, adhesive gel, etc. whichprevents the drug depot from being removed from that site by the venoussystemic circulation or otherwise dispersed too widely, which reducesthe desired therapeutic effect. For example, after hours or days, thedrug depot may degrade, thereby allowing the drug depots (e.g., strips,ribbon-like strips, etc.) to begin releasing the therapeutic agent. Thestrips may be formed from an insoluble or inert substance, but solubleor active once it comes into contact with the target tissue site.Likewise, the drug depot may comprise a substance that dissolves ordisperses within the tissue. As the drug depot begins to dissolve withinhours to days, the drug depots (e.g., strips) are exposed to body fluidsand begin releasing their contents. The drug depot can be formulated tooptimize exposure time of the drug depot and release of the therapeuticagent from the drug depot.

In various embodiments, the drug depot (e.g., gel) is flowable and canbe injected, sprayed, instilled, and/or dispensed to, on or in thetarget site. “Flowable” means that the gel formulation is easy tomanipulate and may be brushed, sprayed, dripped, painted, injected,shaped and/or molded at or near the target site as it coagulates.“Flowable” includes formulations with a low viscosity or water-likeconsistency to those with a high viscosity, such as a paste-likematerial. In various embodiments, the flowability of the formulationallows it to conform to irregularities, crevices, cracks, and/or voidsin the site. For example, in various embodiments, the gel may be used tofill one or more voids in an osteolytic lesion.

In various embodiments, the drug depot comprises poly(alpha-hydroxyacids), PLGA, D,L-lactide-glycolide-ε-caprolactone, PLA, PG,polyethylene glycol conjugates of poly(alpha-hydroxy acids),polyorthoesters, polyaspirins, polyphosphagenes, collagen, starch,pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates,albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate,d-alpha tocopheryl succinate, D,L-lactide, D-lactide, L-lactide,D,L-lactide-caprolactone, D,L-lactide-glycolide-caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG(poly(d,l-lactide-co-glycolide), PLA-PLGA, poloxamer 407, PEG-PLGA-PEGtriblock copolymers, SAIB (sucrose acetate isobutyrate) or combinationsthereof. These one or more components allow the therapeutic agent to bereleased from the drug depot in a controlled and/or sustained manner.For example, the drug depot containing the therapeutic agent and apolymer matrix can be injected at the target site and the polymer matrixbreaks down over time (e.g., hours, days) on or within the target sitereleasing bupivacaine and optionally additional therapeutic agents.Thus, the administration of the drug depot can be localized and occurover a period of time (e.g., at least one day to about 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29 and 30 days).

The terms “sustained release” or “sustain release” (also referred to asextended release or controlled release) are used herein to refer to oneor more therapeutic agent(s) that is introduced on or into the body of ahuman or other mammal and continuously releases a stream of one or moretherapeutic agents over a predetermined time period and at a therapeuticlevel sufficient to achieve a desired therapeutic effect throughout thepredetermined time period. Reference to a continuous release stream isintended to encompass release that occurs as the result ofbiodegradation in vivo of drug depot, or a matrix or component thereof,or as the result of metabolic transformation or dissolution of thetherapeutic agent(s) or conjugates of therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example, a bolus or immediate release formulation of bupivacaine maybe placed at or near the target site and a sustain release formulationmay also be placed at or near the same site. Thus, even after the bolusbecomes completely accessible, the sustain release formulation wouldcontinue to provide the active ingredient for the intended site.

In various embodiments, the drug depot is designed to cause an initialburst dose of therapeutic agent within the first 48 hours or 24 hoursafter administration. “Initial burst” or “burst effect” or “bolus dose”refers to the release of therapeutic agent from the drug depot duringthe first 48 hours or 24 hours after the drug depot comes in contactwith an aqueous fluid (e.g., fluid at a wound site, synovial fluid,cerebral spinal fluid, etc.). In some embodiments, the drug depot isdesigned to avoid this initial burst effect.

In various embodiments, the drug depot contains one or more differentrelease layer(s) that releases a bolus dose of bupivacaine orpharmaceutically acceptable salt thereof (e.g., 100 mg to 800 mg,400-800 mg, or 100 mg to 200 mg at a target site) and one or moresustain release layer(s) that releases an effective amount ofbupivacaine or pharmaceutically acceptable salt thereof over a period of3 to 30 days, 3 to 10 days, or 7 to 10 days. In various embodiments, theone or more immediate release layer(s) comprise PLGA, which degradesfaster than the one or more sustain release layer(s), which comprisesPLA, which degrades at a slower rate than the PLGA.

In various embodiments, when the drug depot comprises a gel, the gel mayhave a pre-dosed viscosity in the range of about 1 to about 500centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After thegel is administered to the target site, the viscosity of the gel willincrease.

In one embodiment, the gel may be an adherent gel, which comprises atherapeutic agent that is evenly distributed throughout the gel. The gelmay be of any suitable type, as previously indicated, and should besufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted site. The gel may, for example, solidify uponcontact with the targeted site or after deployment from a targeteddelivery system. The targeted delivery system may be, for example, asyringe, a catheter, needle or cannula or any other suitable device. Thetargeted delivery system may inject or spray the gel into or on thetargeted site. The therapeutic agent may be mixed into the gel prior tothe gel being deployed at the targeted site. In various embodiments, thegel may be part of a two-component delivery system and when the twocomponents are mixed, a chemical process is activated to form the geland cause it to stick or adhere to the target site.

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofa target site such as a tissue (e.g., recesses and/or projections inbone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be used in someinstances, for example, when applying the formulation via spray.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer, versus non-polymer). For example, in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel, which includes a high molecular weight polymer, tends tocoagulate or solidify more quickly than a polymeric composition, whichincludes a low-molecular weight polymer. Polymeric gel formulations,which include high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel, which include a low-molecularweight polymer.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and longer degradationtime). Typically, a gel with a high molecular weight provides a strongermatrix and the matrix takes more time to degrade. In contrast, a gelwith a low molecular weight degrades more quickly and provides a softermatrix. In various embodiments, the gel has a molecular weight, as shownby the inherent viscosity, from about 0.10 dL/g to about 1.2 dL/g orfrom about 0.10 dL/g to about 0.40 dL/g. Other IV ranges include but arenot limited to about 0.05 to about 0.15 dL/g, about 0.10 to about 0.20dL/g, about 0.15 to about 0.25 dL/g, about 0.20 to about 0.30 dL/g,about 0.25 to about 0.35 dL/g, about 0.30 to about 0.35 dL/g, about 0.35to about 0.45 dL/g, about 0.40 to about 0.45 dL/g, about 0.45 to about0.50 dL/g, about 0.50 to about 0.70 dL/g, about 0.60 to about 0.80 dL/g,about 0.70 to about 0.90 dL/g, and about 0.80 to about 1.00 dL/g.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, from about 15 cps to about 75 cps at room temperature, whichallows it to be sprayed at or near the target site.

In various embodiments, the drug depot may comprise material to enhanceviscosity and control the release of the drug. Such material mayinclude, for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcelluloseand salts thereof, Carbopol, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethyl-methacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, PEG 200, PEG 300, PEG 400, PEG500, PEG 550, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450,PEG 3350, PEG 4500, PEG 8000 or combinations thereof. For example, invarious embodiments, the drug depot comprises from about 25% to 75% byweight bupivacaine, about 15% to 75% by weightD,L-lactide-glycolide-caprolactone, and about 5% to 10% by weight of PEG300. The drug depot can also comprise from about 1% to 15% NMP.

The drug depot release profile can also be controlled, among otherthings, by controlling the particle size distribution of the componentsof the drug depot. In various embodiments, the particle sizedistribution of the components of the drug depot (e.g., bupivacaine,gel, etc.) may be in the range of from about 10 μM to 200 μM so that thedrug depot can easily be delivered to or at or near the target site byinjection, spraying, instilling, etc. In various embodiments, theparticle size may be 10 μM, 13 μM, 85 μM, 100 μM, 151 μM, 200 μM and allsubranges therebetween.

In various embodiments, the drug depot may comprise a hydrogel made ofhigh molecular weight biocompatible elastomeric polymers of synthetic ornatural origin. A desirable property for the hydrogel to have is theability to respond rapidly to mechanical stresses, particularly shearsand loads, in the human body.

Hydrogels obtained from natural sources are particularly appealing sincethey are more likely to be biodegradable and biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid andpoly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol(e.g., PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with bupivacaine. In one embodiment, themicrospheres provide for a sustained release of the bupivacaine. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the bupivacaine; the microspheres thus donot release the bupivacaine until they have been released from the gel.For example, a gel may be deployed around an infected target tissue site(e.g., a nerve root). Dispersed within the gel are a plurality ofmicrospheres that encapsulate the desired therapeutic agent. Certain ofthese microspheres degrade once released from the gel, thus releasingthe bupivacaine.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding target site, and hence disperse thebupivacaine. In some situations, this may be desirable; in others, itmay be more desirable to keep the bupivacaine tightly constrained to awell-defined target site. The present invention also contemplates theuse of adherent gels to so constrain dispersal of the therapeutic agent.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to the target site. The cannula or needle of the drug depot deviceis designed to cause minimal physical and psychological trauma to thepatient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site of administration. Some examples of lengths of thecannula or needle may include, but are not limited to, from about 50 to150 mm in length, for example, about 65 mm for epidural pediatric use,about 85 mm for a standard adult and about 110 mm for an obese adultpatient. The thickness of the cannula or needle will also depend on thesite of administration or target site. In various embodiments, thethickness includes, but is not limited to, from about 0.05 to about1.655. The gauge of the cannula or needle may be the widest or smallestdiameter or a diameter in between for insertion into a human or animalbody. The widest diameter is typically about 14 gauge, while thesmallest diameter is about 22 gauge. In various embodiments the gauge ofthe needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the target site, so that the user may accurately position the depotat or near the site using any of the numerous diagnostic imagingprocedures. Such diagnostic imaging procedures include, for example,X-ray imaging or fluoroscopy. Examples of such radiographic markersinclude, but are not limited to, barium, calcium, and/or metal beads orparticles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, x-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproducing cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including, but not limited to, gassterilization, such as, for example, with ethylene oxide or steamsterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to administer the drug depot (e.g., ribbon-like strips). Thekit may include the drug depot device in a first compartment. The secondcompartment may include a canister holding the drug depot and any otherinstruments needed for the drug delivery. A third compartment mayinclude gloves, drapes, wound dressings and other procedural suppliesfor maintaining sterility of the administration process, as well as aninstruction booklet. A fourth compartment may include additionalcannulas and/or needles. Each tool may be separately packaged in aplastic pouch that is radiation sterilized. A cover of the kit mayinclude illustrations of the administration procedure and a clearplastic cover may be placed over the compartments to maintain sterility.

In various embodiments, a method for delivering bupivacaine into atarget site of a patient is provided. The target site is an infectedsite or a potentially infected site. The method comprises inserting acannula or needle at or near a target site and administering the drugdepot containing the bupivacaine at the target site of the patient. Invarious embodiments, to administer the drug depot to the desired site,first the cannula or needle can be inserted through the skin and softtissue down to the target site and the drug depot administered (e.g.,injected, implanted, instilled, sprayed, etc.) at or near the targetsite. In those embodiments where the drug depot is separate from thegel, first the cannula or needle can be inserted through the skin andsoft tissue down to the site of injection and one or more base layer(s)of gel can be administered to the target site. Following administrationof the one or more base layer(s), the drug depot can be administered onor in the base layer(s) so that the gel can hold the depot in place orreduce migration. If required, a subsequent layer or layers of gel canbe applied on the drug depot to surround the depot and further hold itin place. Alternatively, the drug depot may be implanted or injectedfirst and then the gel placed (e.g., brushed, dripped, injected, orpainted, etc.) around the drug depot to hold it in place. By using thegel, accurate and precise administration of a drug depot can beaccomplished with minimal physical and psychological trauma to thepatient. In various embodiments, the drug depot can be sutured to thetarget site or alternatively the drug depot can be administered, withoutsuturing. For example, in various embodiments, the drug depot can be astrip-shaped or ribbon-shaped depot and placed at the target site,before, during or after surgery. As another example, the drug depot canbe delivered in the form of a gel via a syringe or other injectabledelivery directly to the target site, before, during or after surgery.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through a cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

Treating or treatment of an infection or condition refers to executing aprotocol, which may include administering one or more drugs to a patient(human, other normal or otherwise), in an effort to alleviate signs orsymptoms of the infection. Alleviation can occur prior to signs orsymptoms of the infection or condition appearing, as well as after theirappearance. Thus, “treating” or “treatment” may include “preventing” or“prevention” of an infection or an undesirable condition. In addition,“treating” or “treatment” does not require complete alleviation of signsor symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducing”includes a decrease in the condition and does not require completealleviation of the signs or symptoms, and does not require a cure. Invarious embodiments, reducing an infection includes even a marginaldecrease in the infection. By way of example, the administration of oneor more effective dosages of bupivacaine may be used to prevent, treator relieve an infection incidental to surgery.

“Localized” delivery includes delivery where one or more drugs aredeposited within, at or near a tissue. For example, localized deliveryincludes delivery to a nerve root of the nervous system or a region ofthe brain, or in close proximity (within about 10 cm, or preferablywithin about 5 cm, for example) thereto. “Targeted delivery system”provides delivery of one or more drugs depots (e.g., gels or depotdispersed in the gel, etc.) having a quantity of therapeutic agent thatcan be deposited at or near a target tissue site as needed for treatmentof an infection incidental to surgery.

FIG. 1 illustrates a number of common locations within a patient thatmay be sites at which surgery took place. It will be recognized that thelocations illustrated in FIG. 1 are merely exemplary of the manydifferent locations within a patient that may be at which surgery tookplace. For example, surgery may be required at a patient's knees 21,hips 22, fingers 23, thumbs 24, neck 25, and spine 26. Thus, during orfollowing these surgeries, the patient may be experiencing an infectionat any of these sites.

The target site includes any site which is a site of infection orpotential infection. For example, the target site can be a wound sitethat is infected or has the potential to become infected. A drug depotas provided herein can be administered to the wound site to treat anexisting infection or prevent an infection if no infection exists. Thedrug depot can be administered in many forms as provided herein. Oneembodiment contemplates a bandage comprising the depot which would coverthe wound site. The depot can provide immediate relief to an existinginfection followed by continuous treatment of the infection to reduce oreliminate the infection. If no infection exists in the wound site, thedepot can immediately work to reduce the likelihood of infection orprevent an infection from occurring at the wound site.

The target site can be any site such as a muscle, a ligament, a tendon,cartilage, a spinal disc, the spinal foraminal space near the spinalnerve root, a facet or synovial joint, or the spinal canal. These sitesmay be infected during a surgical procedure (e.g., hernia repair,orthopedic or spine surgery, etc.) or may have the potential to beinfected during a surgical procedure. Surgical procedures include anyprocedure that penetrates beneath the skin. Surgical procedures alsoinclude arthroscopic surgery, an excision of a mass, spinal fusion,thoracic, cervical, or lumbar surgery, pelvic surgery or a combinationthereof. A drug depot can be administered to these surgical sites totreat an existing infection or prevent an infection if no infectionexists.

One embodiment where the depot is suitable for use in infectionmanagement is illustrated in FIG. 2. Schematically shown in FIG. 2 is adorsal view of the spine and sites where the drug depot may be insertedusing a syringe, cannula or needle beneath the skin 34 to a spinal site32 (e.g., spinal disc space, spinal canal, soft tissue surrounding thespine, nerve root, etc.) and one or more drug depots 28 and 32 aredelivered to various sites along the spine. In this way, when severaldrug depots are to be implanted, they are implanted in a manner thatoptimizes location, accurate spacing, and drug distribution.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including, but notlimited to, at least one muscle, ligament, tendon, cartilage, spinaldisc, spinal foraminal space, near the spinal nerve root, or spinalcanal. In various embodiments, the drug depot containing bupivacaine canbe administered to the patient intra-operatively, intravenously,intramuscularly, continuous or intermittent infusion, intraperitoneal,intrasternal, subcutaneously, intrathecally, intradiskally,peridiskally, epidurally, perispinally, intraarticular injection,parenterally, or via combinations thereof. In some embodiments, theinjection is intrathecal, which refers to an injection into the spinalcanal (intrathecal space surrounding the spinal cord). An injection mayalso be into a muscle or other tissue.

In some embodiments, it is preferable to co-administer bupivacaine withan antagonist to counteract undesirable effects. Exemplary antagonistsinclude but are not limited to phentolamine, yohimbine, tolazoline andpiperoxane. Additionally, compounds such as 5-fluorodeoxyuridine (FUDR)and 3,4 dehydroprolene may also be included. These compounds may preventor reduce glial and fibroblastic scar formation associated with sometypes of surgeries.

In some embodiments, the drug depot is suitable for parenteraladministration. Parenteral administration may include, for example, aninfusion pump that administers a pharmaceutical composition (e.g.,anesthetic and anti-inflammatory combination) through a catheter nearthe spine or one or more inflamed joints, an implantable mini-pump thatcan be inserted at or near the target site, an implantable controlledrelease device or sustained release delivery system that can release acertain amount of the drug per hour or in intermittent bolus doses. Oneexample of a suitable pump for use is the SynchroMed® (Medtronic,Minneapolis, Minn.) pump. This pump has three sealed chambers. Onecontains an electronic module and battery. The second contains aperistaltic pump and drug reservoir. The third contains an inert gas,which provides the pressure needed to force the pharmaceuticalcomposition into the peristaltic pump. To fill the pump, thepharmaceutical composition is injected through the reservoir fill portto the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously, atspecific times, or at set intervals between deliveries.

In various embodiments, where the target site comprises blood vessels, avasoconstrictor may be employed in the drug depot. When thevasoconstrictor is released, it lengthens the duration of the anestheticresponse and reduces the systemic uptake of the anesthetic agent. Theanesthetic may be, for example, bupivacaine, and the vasoconstrictor maybe, for example, epinephrine or phenylephrine.

The term “patient” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

Method of Making Depots

In various embodiments, the drug depot comprising the analgesic, localanesthetic or pharmaceutically acceptable salt thereof can be made bycombining a biocompatible polymer and a therapeutically effective amountof the analgesic, local anesthetic or pharmaceutically acceptable saltthereof and forming the drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example, abiocompatible polymer and/or a therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: an analgesic or localanesthetic, other therapeutic agent(s) and other optional additives suchas radiographic agent(s), etc. in dissolved or dispersed form. Thisresults in a polymeric matrix region containing these species aftersolvent removal. In other embodiments, a solution containing solventwith dissolved or dispersed therapeutic agent is applied to apre-existing polymeric region, which can be formed using a variety oftechniques including solution processing and thermoplastic processingtechniques, whereupon the therapeutic agent is imbibed into thepolymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: an analgesicor local anesthetic, optional additional therapeutic agent(s),radiographic agent(s), and so forth. The resulting mixture is thenshaped into a drug depot. The mixing and shaping operations may beperformed using any of the conventional devices known in the art forsuch purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, if the local anesthetic is bupivacaine, it mayundergo substantial degradation under ordinary thermoplastic processingconditions. Hence, processing is preferably performed under modifiedconditions, which prevent the substantial degradation of the therapeuticagent(s). Although it is understood that some degradation may beunavoidable during thermoplastic processing, degradation is generallylimited to 10% or less. Among the processing conditions that may becontrolled during processing to avoid substantial degradation of thetherapeutic agent(s) are temperature, applied shear rate, applied shearstress, residence time of the mixture containing the therapeutic agent,and the technique by which the polymeric material and the therapeuticagent(s) are mixed.

Mixing or compounding the biocompatible polymer with therapeuticagent(s) and any additional additives to form a substantially homogenousmixture thereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with a therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the drug depot. Conversely, in anotherembodiment, the biocompatible polymer can be precompounded with thetherapeutic agent under conditions of reduced temperature and mechanicalshear. This precompounded material is then mixed with, for example, aradio-opacifying agent, also under conditions of reduced temperature andmechanical shear, and the resulting mixture is shaped into the drugdepot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear, in various embodiments, thePGLA or PLA can be premixed with the radio-opacifying agent attemperatures of about, for example, 150° C. to 170° C. The therapeuticagent is then combined with the premixed composition and subjected tofurther thermoplastic processing at conditions of temperature andmechanical shear that are substantially lower than is typical for PGLAor PLA compositions. For example, where extruders are used, barreltemperature, volumetric output are typically controlled to limit theshear and therefore to prevent substantial degradation of thetherapeutic agent(s). For instance, the therapeutic agent and premixedcomposition can be mixed/compounded using a twin screw extruder atsubstantially lower temperatures (e.g., 100-105° C.), and usingsubstantially reduced volumetric output (e.g., less than 30% of fullcapacity, which generally corresponds to a volumetric output of lessthan 200 cc/min). It is noted that this processing temperature is wellbelow the melting points of local anesthetics such as bupivacaine,because processing at or above these temperatures will result insubstantial therapeutic agent degradation. It is further noted that incertain embodiments, the processing temperature will be below themelting point of all bioactive compounds within the composition,including the therapeutic agent. After compounding, the resulting depotis shaped into the desired form, also under conditions of reducedtemperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvent system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., ribbon, pellet, strip, etc.) is cooled. Examples ofcooling processes include air cooling and/or immersion in a coolingbath. In some embodiments, a water bath is used to cool the extrudeddepot. However, where the therapeutic agent is water-soluble, theimmersion time should be held to a minimum to avoid unnecessary loss oftherapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, a local anesthetic such asbupivacaine is used and mixed or sprayed with PLGA,poly(D,L-lactide-caprolactone) polymer, and/orpoly(D,L-lactide-glycolide-caprolactone) polymer and the resulting depotmay be formed by extrusion and dried.

In some formulations, there may be 55-65% bupivacaine, 25-35% PLGA and5-15% mPEG. Some of these formulations will release between 10 and 30%of the active ingredient on day 1 and all or substantially all of theactive ingredient by day 10. Some of these formulations will releasebetween 15 and 25% of the active ingredient on day 1 and all orsubstantially all of the product by day 10.

In still other formulations, there may be 55-65% bupivacaine, 25-35%DL-G-CL, 6% PEG 300 and 13% NMP. Some of these formulations will releasebetween 10 and 30% of the active ingredient on day 1 and all orsubstantially all of the active ingredient by day 10. Some of theseformulations will release between 10 and 15% of the active ingredient onday 1 and all or substantially all of the product by day 10.

In another embodiment, a drug depot useful for reducing, preventing ortreating an infection in a patient in need of such treatment isprovided. The drug depot comprises a therapeutically effective amount ofbupivacaine or pharmaceutically acceptable salt thereof. The depot isadministered at a target site to reduce, prevent or treat infectionswherein the drug depot comprises (i) one or more immediate releaselayer(s) that is capable of releasing about 5% to about 50% of thebupivacaine or pharmaceutically acceptable salt thereof relative to atotal amount of the bupivacaine or pharmaceutically acceptable saltthereof loaded in the drug depot over a first period of up to 48 hours,a first period of up to 24 hours, or a first period of about 24 to 48hours and (ii) one or more sustain release layer(s) that is capable ofreleasing about 50% to about 95% of the bupivacaine or pharmaceuticallyacceptable salt thereof relative to a total amount of the bupivacaine orpharmaceutically acceptable salt thereof loaded in the drug depot over asubsequent period of up to 4 to 30 or 4 to 10 days. The immediaterelease layer allows for the release of bupivacaine immediately to treatan infection followed by sustained release of bupivacaine from thesustain release layer which provides sustained relief of the infection.The one or more immediate release layer(s) comprise one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof, and the one or more sustain release layer(s)comprise one or more of poly(lactide-co-glycolide), polylactide,polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof.

In still another embodiment, a method of reducing an infection in apatient in need of such treatment is provided. The method comprisesdelivering one or more biodegradable drug depots comprising atherapeutically effective amount of bupivacaine or pharmaceuticallyacceptable salt thereof to a target tissue site beneath the skin before,during or after surgery, wherein the drug depot is capable of releasingan initial bolus dose of an effective amount of bupivacaine orpharmaceutically acceptable salt thereof at the site beneath the skinfollowed by a sustained release dose of an effective amount ofbupivacaine or pharmaceutically acceptable salt thereof over a period of4 to 30 days, 4 to 10 days, or 5 to 7 days. The initial bolus doseprovides immediate relief to the infection followed by continuoustreatment reducing the infection. The drug depot may comprise a polymerand the polymer may comprise one or more of poly(lactide-co-glycolide),polylactide, polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. Bupivacaine may be in the form of a salt and/or inthe form of a base. The polymer may be biodegradable. The drug depot maybe a ribbon-like strip. The drug depot is capable of releasing about 40to 90% of the bupivacaine or pharmaceutically acceptable salt thereofrelative to a total amount of bupivacaine or pharmaceutically acceptablesalt thereof loaded in the drug depot over the period of 4 to 10 daysafter the drug depot is administered to the target tissue site.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES Example 1

A number of formulations of bupivacaine were prepared according to thefollowing procedures:

Materials: Poly(D,L-lactide-co-caprolactone) having a 25:75 lactide tocaprolactone molar ratio (25:75 DL-CL), an intrinsic viscosity of 0.8dL/g and a molecular weight of 95 kDa was purchased from LakeshoreBiomaterials (Birmingham, Ala.).Poly(D,L-lactide-co-glycolide-co-caprolactone) having a 30:20:50 lactideto glycolide to caprolactone molar ratio (30:20:50 DL-G-CL), anintrinsic viscosity of 0.05 dL/g to 0.15 dL/g and a molecular weight of10 kDa was purchased from Lakeshore Biomaterials (Birmingham, Ala.).Bupivacaine Base was purchased from Orgamol (Switzerland). Polyethyleneglycol (PEG) having an average molecular weight of 300-400 g/mol waspurchased from Spectrum Chemicals, n-methylpyrrolidone (NMP) having anaverage molecular weight of 99 g/mol was purchased from Fisher, andacetone was also purchased from Sigma-Aldrich.

Methods:

Preparation of bupivacaine base/25:75 DL-CL strip implant: The 25:75DL-CL polymer was added to a glass vial and heated to either 100° C.(below drug melt temp) or 110° C. (above drug melt temp). Bupivacainebase was added to the melted polymer and mixed with a spatula untilvisually homogeneous. The resulting blend was removed from the glassvial and pressed into a thin film (0.4-0.6 mm thickness) using a CarverPress. The Carver Press was operated at 45° C. and 6000-8000 psipressure. The thin film was cut to form a strip of the desireddimensions with a sharp blade. The dimensions of the strip were 9 mm inlength, 0.4 to 1 mm in thickness and 1.5 to 3 mm in width.

Preparation of bupivacaine base/30:20:50 DL-G-CL injectable paste/gelformulation: The polymer (318 mg), PEG 300 (92 mg) and NMP (199 mg) wereadded to a glass vial and heated to 93° C. for approximately 10 minutes.The bupivacaine (911 mg) was added to the mixture and maintained at 93°C. for 20 minutes while being stirred/vortexed to get the drug todissolve. Vail was removed from the heat and the mixture was stirred asit cooled to room temperature. The formulation was collected from thevial and added to a 1 mL syringe. The mixture was easily expelled fromthe syringe (no needle attached) when heated to 40° C.

In Vitro drug elution testing of bupivacaine base/25:75 DL-CL ribbonimplant and Bupivacaine base/30:20:50 DL-G-CL injectable gelformulation: The purpose of this procedure was to measure the release ofbupivacaine from a polymer strip and a gel formulation into a receivingfluid PBS buffer, pH 7.4. The in vitro release procedure consisted ofplacing a known mass of implant or gel into an apparatus containing thereceiving fluid. The in vitro release apparatus consisted of a 60 mlglass bottle. A receiving fluid in the amount of 30 ml was added to eachsample bottle. During the release study, the apparatus was placed in anincubator maintained at 37±2° C. At predetermined intervals, samples ofthe receiving fluid were removed and analyzed for bupivacaineconcentration by HPLC.

Elution profile: These formulations of bupivacaine were tested inBrennan rats to determine their in vitro elution. FIGS. 5 and 6 show theaverage cumulative release profiles of these bupivacaine formulations.Also, the results are summarized below in Table 1:

TABLE 1 Active Formulation Wt. % of Handling In vitro Elution NumberPolymer Bupivacaine Excipient Property Profile 1 2575 DL-CL 63% NoneMalleable Day 1 burst release of 8E (bupivacaine 22%. 97% eluted bybase) day 10. 2 30:20:50 DL- 60% 6% PEP Injectable Day 1 release of 12%,G-CL 1E (bupivacaine 300, Paste 75% of the drug eluted base) 13% NMP byday 10 DL-CL is an abbreviation for poly(DL-lactide-co-caprolactone)polymer.

For formulation 1, there was a concern that the co-polymer could take upto 6-8 months to fully degrade. No excipient was needed because thebupivacaine was melted before it was mixed with the polymer. Themalleability was of sufficient flexibility to permit extrusion to astrip or ribbon dosage form.

For formulation 2, the degradation of the polymer was less than onemonth.

Example 2

A number of formulations of bupivacaine were prepared according to thefollowing procedures:

Materials: Poly(D,L-lactide-co-glycolide) having a 50:50 lactide toglycolide molar ratio (PLGA 50501A), an intrinsic viscosity of 0.12 andacid end capped polymer chain ends was purchased from LakeshoreBiomaterials (Birmingham, Ala.). Bupivacaine Base was purchased fromOrgamol (Switzerland). Bupivacaine HCl was purchased from SpectrumChemicals (Gardena, Calif.). Methoxy polyethylene glycol (mPEG) havingan average molecular weight of 550 was purchased from Sigma-Aldrich.Methanol and acetone was also purchased from Sigma-Aldrich.

Methods:

Preparation of spray dried bupivacaine base/PLGA50501A: Bupivacaine baseand PLGA50501A were both dissolved in acetone to yield a 10% (w/w)solution. A mixture of 65.2% bupivacaine base solution and 34.8%PLGA50501A solution was spray dried in the Buchi Spray Dryer. Theprocessing parameters were set as follows: inlet temp. (70° C.),aspirator (80%), nitrogen inlet (50 mm), spray flow rate (80 mL/hr) andultrasonic generator (0.8 watts). The spray dried powder was collectedand dried for an additional 24 hours at 30° C. and 15 mmHg vacuum.

Preparation of spray dried bupivacaine HCl: Bupivacaine HCl wasdissolved in methanol to yield a 10% (w/w) solution and the solution wasspray dried in the Buchi Spray Dryer. The processing parameters were setas follows: inlet temp. (70° C.), aspirator (80%), nitrogen inlet (50mm), spray flow rate (80 mL/hr) and ultrasonic generator (0.8 watts).The spray dried powder was collected and dried for additional 24 hoursat 70° C. and 15 mm Hg vacuum.

Preparation of melt extruded rods: Three formulations were prepared formelt extrusion. All three formulations contained PLGA50501A ground intopowder using a Retsch (Retsch GmbH, Germany) rotor mill with an 80micrometer sieve filter. The first such formulation contained 30% (w/w)ground PLGA50501A, 60% (w/w) spray dried bupivacaine HCl, and 10% (w/w)mPEG (60% bupivacaine HCl). The second formulation contained 90% (w/w)spray dried bupivacaine base/PLGA50501A and 10% (w/w) mPEG (60%bupivacaine base). The last formulation contained 90% (w/w) groundPLGA50501A and 10% (w/w) mPEG (vehicle polymer). The last formulationwas not tested.

The first two formulations were dry mixed with a spatula prior to beingfeed into a Haake Mini-Lab twin screw extruder (Thermo FischerScientific, Waltham, Mass.). The extruder settings were as follows: 105°C. and 30 RPM for the 60% bupivacaine HCl formulation, and 85° C. and 30RPM for the 60% bupivacaine base formulation. The first two formulationswere extruded out of a 1.5 mm diameter die.

Strip preparation: Extruded formulations were pressed into sheets of adesired thickness using a Carver Laboratory Heat Press (Carver, Inc.,Wabash, Ind.) set at 50° C. The sheets were cut by razor blades to formstrips of the desired dimensions. The dimensions of each formulationwere (length by width by height or L×W×H): 60% bupivacaine base (9 mm×3mm×1 mm), and 60% bupivacaine HCl (9 mm×3 mm×1 mm).

In Vitro drug elution testing: Each strip formulation was tested intriplicate and placed in 20 mL scintillation vials for drug elutiontesting. The 60% bupivacaine HCl and 60% bupivacaine base strips (orribbons) were incubated in 10 mL of phosphate buffer with 0.5% (w/w)sodium dodecyl sulfate pH 7.4 at 37° C. under mild agitation. Atpre-selected times, the buffer was removed for analysis and replacedwith fresh buffer medium. The drug content was quantified at 260 nm forbupivacaine by Molecular Devices SpectraMax M2 (Sunnyvale, Calif.) platereader.

Elution profile: These formulations of bupivacaine were tested inBrennan rats to determine the in vitro elution. FIGS. 3 and 4 show therelease rate of the bupivacaine 3 formulation (labeled as BupivacaineHCl in the figures) and the bupivacaine 4 formulation (labeled asBupivacaine Base in the figures) from Table 2 in micrograms andpercentages. The results are also summarized below in Table 2:

TABLE 2 Active wt. % In vitro Formulation Polymer of Excipient Handlingelution Number (wt. %) Bupivacaine (wt. %) Property profile bupivacaine3 30% PLGA 60% 10% mPEG Sticky, Day 1 release of 50501 A (bupivacainemalleable 47%; by day 7, HCl) 100% released bupivacaine 4 30% PLGA 60%10% mPEG Sticky, Day 1 release of 50501 A (bupivacaine malleable 20%; byday 9, base) 70% released bupivacaine 5 PLA-C12 gel 30% None InjectableDay 1 burst (bupivacaine release of 30%; base) by day 10, 70% of thedrug eluted

For the bupivacaine 3 and 4 formulations, the polymer degraded in lessthan one month. The handling property was of a nature to enable amalleable and formable formulation product that could be extruded to astrip-like (ribbon) dosage form.

For the bupivacaine 5 formulation, the degradation of the polymer tookat least a couple of months.

Example 3

A number of additional bupivacaine base formulations were prepared andtheir cumulative in vitro release profiles was measured.

Materials: Poly(D,L-lactide-co-caprolactone) having a 25:75 lactide tocaprolactone molar ratio (25:75 DL-CL), an intrinsic viscosity of 0.8dL/g and a molecular weight of 95 kDa was purchased from LakeshoreBiomaterials (Birmingham, Ala.).Poly(D,L-lactide-co-glycolide-co-caprolactone) having a 30:20:50 lactideto glycolide to caprolactone molar ratio (30:20:50 DL-G-CL), anintrinsic viscosity of 0.05 dL/g to 0.15 dL/g and a molecular weight of10 kDa was purchased from Lakeshore Biomaterials (Birmingham, Ala.).Bupivacaine base was purchased from Orgamol (Switzerland). The PEGpolymers having average molecular weights of 300, 1,500 and 8,000 werepurchased from Spectrum Chemicals, n-methylpyrrolidone (NMP) having anaverage molecular weight of 99 g/mol was purchased from Fisher, andacetone was also purchased from Sigma-Aldrich. Labrosol consists ofPEG-8 caprylic/capric glycerides was purchased from Gattefosse, USA(Paramus, N.J.). Trehalose having an average molecular weight of 324g/mol was purchased from Sigma-Aldrich (St. Louis, Mo.).

Methods:

Preparation of bupivacaine base/DL-CL strips: The 10:90, 25:75 or 65:35DL-CL polymer were each added to glass vials and heated to either 100°C. (below drug melt temp) or 110° C. (above drug melt temp). Bupivacainebase was added to the melted polymers and mixed with a spatula untilvisually homogeneous. The resulting blend was removed from the glassvial and pressed into a thin film (0.4-0.6 mm thickness) using a CarverPress. The Carver Press was operated at 45° C. and 6000-8000 psipressure. The thin film was cut to form strips (ribbons) of the desireddimensions with a sharp blade. The dimensions of the implants were 9 mmin length, 1.5 to 3 mm in width and 0.5 to 1 mm in thickness.

In Vitro drug elution testing of bupivacaine base/25:75 DL-CL ribbons:The purpose of this procedure was to measure the release of bupivacainefrom a polymer formulation into a receiving fluid PBS buffer, pH 7.4.The in vitro release procedure consisted of placing a known mass ofimplant or gel into an apparatus containing the receiving fluid. The invitro release apparatus consisted of a 60 ml glass bottle. A receivingfluid in the amount of 30 ml was added to each sample bottle. During therelease study, the apparatus was placed in an incubator maintained at37±2° C. At predetermined intervals, samples of the receiving fluid wereremoved and analyzed for bupivacaine concentrations by HPLC. The drugloadings for these formulations are summarized in Table 3 below. Inaddition, Table 3 provides a description for each of these bupivacaineformulations.

TABLE 3 Molar Batch Ratio of Drug Load Number Polymer Polymers Excipient(wt. %) Description/Shape 00180-25 DL-CL 10:90 None 62.16 extruded,ribbon shaped 00180-26 5050 4C — None 71.34 extruded, ribbon shaped PEG1500 00180-27 5050 2C — None 58.96 extruded, ribbon shaped PEG 150000180-28 DL-CL 8E 25:75 None 53.83 maleable, formable product 00180-36DL-CL 8E 25:75 None 70.88 maleable, formable product 00180-38 DL-CL 8E25:75 100 mg 57.5 maleable, formable product NMP 00180-39 DL-CL 8E 25:75None 61.7 maleable, formable product 00180-40 DL-CL 8E 25:75 None 60.6maleable, formable product 00180-53 DL-CL 4A 65:35 None 70 very hard,not very formable product 00180-54 DL-CL 5A 25:75 None 70 brittle,crumbly, not formable product 00180-55 DL-CL 5A 25:75 118 mg 65.92maleable, formable product- NMP investigation 00180-56 DL-CL 4A 65:35118 mg 66.19 of lower MW polymers with acid NMP end 00180-57 DL-CL 5A25:75 20.5 mg 60.11 group chemistry NMP 00180-58 DL-CL 4A 65:35 45.6 mg58.37 NMP 00180-79- DL-CL 8E 25:75 2% PEG 62.69 somewhat tacky, easily01 1500 formable initially, after handling for a few minutes, thematerial becomes crumbly 00180-79- DL-CL 8E 25:75 2% PEG 61.9 somewhattacky, easily 02 8000 formable, holds together much better than PEG1500formulation (180-79-01), does not crumble after prolonged handling00180-80- DL-CL 8E 25:75 2% 61.57 easy to handle, smooth texture, 01trehalose, formable 4% NMP 00180-80- DL-CL 8E 25:75 2% CMC, 4 61.03tacky, easy to handle, formable 03 % NMP 00180-80- DL-CL 8E 25:75 4%58.91 tacky, easy to handle, formable 04 labrosol 00180-80- DL-CL 8E25:75 5% 5050 60.49 flaky and crumbly, did not hold 05 20 PEG togetherwell 1500 00180-112 DL-CL 8E 25:75 None 62.03 maleable, formable product

Example 4

Several bupivacaine gel formulations were prepared.

Preparation of PLA Gel: Depolymerization of Polylactic Acid withDodecanol

Polylactic acid (intrinsic viscosity of 5.71 and weight of 15.0 grams),4-dimethylaminopyridine (weight of 9.16 grams), and dodecanol (weight of5.59 grams) were added into a 100 mL round bottom flask, charged, cappedwith a rubber septum and placed in an oil bath at 140° C. The materialswere heated at that temperature for 30 minutes after everything wasmelted and was stirred freely with a magnetic stir bar. After cooling,15 mL of tetrahydrofuran was added into the flask to dissolve thematerials and precipitated by adding heptane. After decanting off thesolvents, the material was dissolved in chloroform (30 mL) and washedwith hydrochloride (1 molar, 20 mL, three times) and brined once. Thesolution was dried over anhydrous sodium sulfate. Yellow oil wasobtained after solvent removal by rota-evaporation. (Mn about 800 g/molby end group analysis by H-NMR)

Method of preparation of bupivacaine gel formulations: The formulationswere prepared to contain 70% (w/w) PLA gel and 30% (w/w) spray driedbupivacaine. For each formulation, the two components were added to a 2cc transfer cup and mixed in a Flacktek, Inc. Speedmixer DAC 150 FVZ for2 minutes. The mixed formulations were each then back loaded into a 1 mLBD syringe with a 18G 1.5 inch blunt tip needle.

In vitro drug elution testing: 100 uL of each of the gel formulationswas injected in a 20 mL scintillation vial for drug elution testing. Theformulations were each tested in triplicate and incubated in 10 mL ofphosphate buffer with 0.5% (w/w) sodium dodecyl sulfate pH 7.4 at 37° C.under mild agitation. At pre-selected times, the buffer was removed foranalysis and replaced with fresh buffer medium. The drug content wasquantified for bupivacaine by a Molecular Devices SpectraMax M2(Sunnyvale, Calif.) plate reader. The resulting formulations included30% bupivacaine. FIGS. 7-9 show the in vitro cumulative percentagerelease of bupivacaine per day for the formulations which are listedbelow in Table 4.

TABLE 4 Formulation ID Drug Load (%) 13335-80-1 30 13335-80-2 3013335-80-3 30 13335-80-4 30 13335-80-5 30 13335-80-6 30 13335-80-7 3013335-88-1 30 13335-88-2 30 13335-88-3 30 13335-88-4 30 13335-88-5 3013699-13-1 30

Example 5

A number of formulations of bupivacaine were prepared according to thefollowing procedures:

Materials: Poly(D,L-lactide-co-glycolide) having a 50:50 lactide toglycolide molar ratio (DLG 50501A), an intrinsic viscosity of 0.12 andacid end capped polymer chain ends was purchased from LakeshoreBiomaterials (Birmingham, Ala.). Bupivacaine base was purchased fromOrgamol (Switzerland). Methoxy polyethylene glycol (mPEG) having anaverage molecular weight of 550 was purchased from Sigma-Aldrich.Methanol and acetone was also purchased from Sigma-Aldrich.

Methods:

Preparation of Spray Dried Bupivacaine Base/DLG 50501A: Bupivacaine baseand DLG 50501A were both dissolved in acetone to yield a 10% (w/w)solution. A mixture of 65.2% bupivacaine base solution and 34.8% DLG50501A solution was spray dried in the Buchi Spray Dryer. The processingparameters were set as follows: inlet temp. (70° C.), aspirator (80%),nitrogen inlet (50 mm), spray flow rate (80 mL/hr) and ultrasonicgenerator (0.8 watts). The spray dried powder was collected and driedfor an additional 24 hours at 30° C. and 15 mm Hg vacuum.

Preparation of Melt Extruded Rods: Several formulations were preparedfor melt extrusion. All formulations contained DLG 50501A ground intopowder using a Retsch (Retsch GmbH, Germany) rotor mill with an 80micrometer sieve filter. All formulations contained 60% (w/w) spraydried bupivacaine base/PLGA50501A.

The formulations were each dry mixed with a spatula prior to being fedinto a Haake Mini-Lab twin screw extruder (Thermo Fischer Scientific,Waltham, Mass.). The extruder settings were as follows: 105° C. and 30RPM for the 60% bupivacaine HCl formulation, and 85° C. and 30 RPM forthe 60% bupivacaine base formulation. The formulations were extruded outof a 1.5 mm diameter die.

Strip Preparation: Extruded formulations were pressed into sheets of adesired thickness using a Carver Laboratory Heat Press (Carver, Inc.,Wabash, Ind.) set at 50° C. The sheets were cut by razor blades to formstrips of the desired dimensions. The dimensions of each of theformulations or strips were 9 mm in length by 3 mm in width by 1 mm inheight.

In Vitro Drug Elution Testing: Each strip formulation was tested intriplicate and placed in 20 mL scintillation vials for drug elutiontesting. The 60% bupivacaine base strips (or ribbons) were incubated in10 mL of phosphate buffer with 0.5% (w/w) sodium dodecyl sulfate pH 7.4at 37° C. under mild agitation. At pre-selected times, the buffer wasremoved for analysis and replaced with fresh buffer medium. The drugcontent was quantified at 260 nm for bupivacaine by Molecular DevicesSpectraMax M2 (Sunnyvale, Calif.) plate reader. FIGS. 10 and 11 show thein vitro cumulative percentage release of bupivacaine per day for theformulations which are listed below in Table 5.

TABLE 5 Ribbon Drug Load Size (mm) ID Number Polymer (%) Excipient (L ×W × H) 13335-76-1 5050 DLG 1A 60 5% mPEG 9 × 3 × 1 13335-76-2 5050 DLG2A 60 5% mPEG 9 × 3 × 1 13335-76-3 5050 DLG 1A 60 7% mPEG 9 × 3 × 113335-83-1 5050 DLG 1A 60 8% mPEG 9 × 3 × 1 13335-83-2 5050 DLG 1A 6010% mPEG  9 × 3 × 1 13335-83-5 5050 DLG 1A 60 8% mPEG 9 × 3 × 1

Example 6

Bupivacaine implants were prepared according to the procedure describedin Example 5 above. The formulation used to prepare the implants isdescribed below in Table 6. In particular, the formulation contained 50wt. % bupivacaine base, 42 wt. % 5050DLG 1A, and 8 wt. % mPEG. Theinherent viscosity of the 5050DLG was 0.05-0.15 and it had an acid endgroup.

TABLE 6 % Drug Ribbon Size (mm) Polymer Polymer Load (%) Excipient (L ×W × H) 5050 DLG 1A 42 50 8% mPEG 9 × 3 × 1

The in vitro cumulative and daily release profile was tested beforesterilization using three strip implants from the formulation describedin Table 6. FIGS. 12A and 12B are in vitro graphic representations ofthe percentage cumulative release of three sterilized bupivacainestrips. As is readily apparent in these figures, each formulationreleased between 65% and 85% of the bupivacaine over 14 days with anaverage of 5%-10% of drug released every day. The average cumulativedrug release of the three strips is shown in FIG. 12B, where 75% of thedrug released in 14 days.

FIGS. 13A and 13B are in vitro graphic representations of the dailyrelease profile of the three sterilized bupivacaine strips and theircumulative average daily release in micrograms per day. As is readilyapparent in these figures, each drug depot had an initial burst effectwith a release of bupivacaine at a dose of about 3500 mcg within 2 days.After the two days, each drug depot released about 500-1000 mcg per dayuntil the drug depot was exhausted at day 14.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. A drug depot useful for reducing, preventing or treating an infection in a patient in need of such treatment, the drug depot comprising a polymer and a therapeutically effective amount of a local anesthetic comprising bupivacaine or pharmaceutically acceptable salt thereof, the drug depot being administered at a site to reduce, prevent or treat an infection, wherein the drug depot is capable of releasing (i) a bolus dose of the local anesthetic or pharmaceutically acceptable salt thereof at the site from a layer, wherein between 15 and 25% of the bupivacaine is released within a 24 hour period and (ii) a sustained release dose of an effective amount of the local anesthetic or pharmaceutically acceptable salt thereof over a period of at least 4 days at the site, wherein the polymer comprises a particle size of about 10 μm to about 40 μm and is capable of degrading in less than 30 days after the drug depot is administered at the site.
 2. A drug depot according to claim 1, wherein the polymer comprises one or more of poly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester, D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-glycolide-co-caprolactone) , polycaprolactone or a combination thereof.
 3. A drug depot according to claim 1, wherein the local anesthetic is released in an amount between 50 and 800 mg per day for a period of 4 to 10 days.
 4. A drug depot according to claim 1, wherein the local anesthetic is present in an amount of about 30 to about 90 wt. % of the drug depot and the polymer is present in an amount of about 10 to about 80 wt. % of the drug depot, and the drug depot further comprises about 0.5 to about 20 wt. % of an excipient.
 5. A drug depot for reducing, preventing or treating an infection in a patient in need of such treatment, the drug depot comprising bupivacaine or a pharmaceutically acceptable salt thereof in an amount from about 30 wt. % to about 90 wt. % of the drug depot, and at least one biodegradable material, wherein the drug depot is capable of releasing the bupivacaine or pharmaceutically acceptable salt thereof over a period of at least 4 days and the drug depot comprises a layer that releases between 15 and 25% of the bupivacaine within a 24hour period, wherein the polymer comprises a particle size of about 10 μm to about 40 μm and is capable of degrading in less than 30 days after the drug depot is administered at the site.
 6. A drug depot according to claim 5, wherein the at least one biodegradable material comprises one or more of poly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester, D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide, poly(D,L-lactide-caprolactone), poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or a combination thereof.
 7. A drug depot according to claim 5, wherein the drug depot releases: (i) a bolus dose of the bupivacaine; and (ii) an effective amount of the bupivacaine over a period of at least four days.
 8. A drug depot useful for reducing, preventing or treating an infection in a patient in need of such treatment, the drug depot comprising a therapeutically effective amount of bupivacaine or pharmaceutically acceptable salt thereof and a polymer; wherein the drug depot is administered at a target site to reduce, prevent or treat an infection, and the drug depot is capable of releasing (i) 30% of the bupivacaine or pharmaceutically acceptable salt thereof relative to a total amount of the bupivacaine or pharmaceutically acceptable salt thereof loaded in the drug depot over a first period of up to 24 hours from a first layer and (ii) about 50% to about 98% of the bupivacaine or pharmaceutically acceptable salt thereof relative to a total amount of the bupivacaine or pharmaceutically acceptable salt thereof loaded in the drug depot over a subsequent period of up to 3 to 10 days, wherein the polymer comprises a particle size of about 10 μm to about 40 μm and is capable of degrading in less than 30 days after the drug depot is administered at the site.
 9. A drug depot according to claim 8, wherein the polymer comprises one or more of poly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester, D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or a combination thereof.
 10. A drug depot according to claim 8, wherein the polymer comprises about 15% to about 55% of the total weight of the drug depot.
 11. A drug depot according to claim 8, wherein the drug depot is capable of releasing between 50 and 800 mg/day of bupivacaine or pharmaceutically acceptable salt thereof.
 12. A drug depot according to claim 1, wherein 25% of the bupivacaine is released within a 24 hour period.
 13. A drug depot according to claim 1, wherein the bupivacaine comprises a bupivacaine base.
 14. A drug depot according to claim 1, wherein the drug depot further comprises trehalose. 